Analysis of the genetic phylogeny of multifocal prostate cancer identifies multiple independent clonal expansions in neoplastic and morphologically normal prostate tissue.
Cooper CS., Eeles R., Wedge DC., Van Loo P., Gundem G., Alexandrov LB., Kremeyer B., Butler A., Lynch AG., Camacho N., Massie CE., Kay J., Luxton HJ., Edwards S., Kote-Jarai Z., Dennis N., Merson S., Leongamornlert D., Zamora J., Corbishley C., Thomas S., Nik-Zainal S., Ramakrishna M., O'Meara S., Matthews L., Clark J., Hurst R., Mithen R., Bristow RG., Boutros PC., Fraser M., Cooke S., Raine K., Jones D., Menzies A., Stebbings L., Hinton J., Teague J., McLaren S., Mudie L., Hardy C., Anderson E., Joseph O., Goody V., Robinson B., Maddison M., Gamble S., Greenman C., Berney D., Hazell S., Livni N., ICGC Prostate Group None., Fisher C., Ogden C., Kumar P., Thompson A., Woodhouse C., Nicol D., Mayer E., Dudderidge T., Shah NC., Gnanapragasam V., Voet T., Campbell P., Futreal A., Easton D., Warren AY., Foster CS., Stratton MR., Whitaker HC., McDermott U., Brewer DS., Neal DE.
Genome-wide DNA sequencing was used to decrypt the phylogeny of multiple samples from distinct areas of cancer and morphologically normal tissue taken from the prostates of three men. Mutations were present at high levels in morphologically normal tissue distant from the cancer, reflecting clonal expansions, and the underlying mutational processes at work in morphologically normal tissue were also at work in cancer. Our observations demonstrate the existence of ongoing abnormal mutational processes, consistent with field effects, underlying carcinogenesis. This mechanism gives rise to extensive branching evolution and cancer clone mixing, as exemplified by the coexistence of multiple cancer lineages harboring distinct ERG fusions within a single cancer nodule. Subsets of mutations were shared either by morphologically normal and malignant tissues or between different ERG lineages, indicating earlier or separate clonal cell expansions. Our observations inform on the origin of multifocal disease and have implications for prostate cancer therapy in individual cases.